WO2006025517A1

WO2006025517A1 - Sodium channel inhibitor

Info

Publication number: WO2006025517A1
Application number: PCT/JP2005/016085
Authority: WO
Inventors: Kazumi Kikuchi; Jiro Fujiyasu; Toshihiro Watanabe; Yukinori Nagakura; Hiroshi Tomiyama; Motoharu Sonegawa; Kazuo Tokuzaki; Yoshinori Iwai
Original assignee: Astellas Pharma Inc.; Kotobuki Pharmaceutical Co., Ltd.
Priority date: 2004-09-03
Filing date: 2005-09-02
Publication date: 2006-03-09
Also published as: JP2008001596A

Abstract

A sodium channel inhibitor containing as an active ingredient a piperidine derivative or a pharmaceutically acceptable salt thereof. Also provided is the derivative or salt. The derivative or salt has a structure in which the piperidine ring is directly bonded to a benzene ring or heteroring and this benzene ring or heteroring is directly bonded to another benzene ring. The compounds not only have a high analgesic effect on neurogenic pains but are reduced in side effects.

Description

Specification

Sodium channel inhibitor

Technical field

[0001] The present invention relates to a sodium channel inhibitor, a novel piperidine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same as an active ingredient. More specifically, a sodium channel inhibitor having a high analgesic effect on neuropathic pain and reduced side effects, a novel piperidine derivative useful as a sodium channel inhibitor, or a pharmaceutically acceptable salt thereof. And a pharmaceutical composition containing the same as an active ingredient.

Background art

[0002] Voltage-dependent sodium channels are proteins that control the generation and propagation of nerve action potentials. The voltage-gated sodium channel has a common structure with six transmembrane domain forces S4 repeated large _a subunit and two small β subunits. The main channel function is a subunit. To date, it is known that there are more than 10 a-subunit subtypes (Goldin AL, Annals of the New York Academy of Sciences 868: 38-50, 1999). Each voltage-gated sodium channel subtype has a different distribution in the central and peripheral nervous tissues. They regulate nerve excitability and play an important role in regulating the physiological functions of each tissue. It has also been suggested to be deeply involved in various pathological conditions (Goldin AL, Annual Review of Physiology 63: 871-894, 2001).

In recent years, it has become clear that voltage-gated sodium channels are deeply involved in pain neurotransmission, and sodium channel agonists are expected to be excellent pain therapeutic agents, particularly neuropathic pain therapeutic agents. (Taylor CP, Current Pharmaceutical Design 2: 375-38 8, 1996).

[0003] Neuropathic pain means pain due to peripheral or central nervous system dysfunction, including diabetic neuropathic pain, cancer pain, trigeminal neuralgia, phantom limb pain, postherpetic pain, thalamic pain, etc. Can be mentioned. The clinical picture of neuropathic pain is painful tightening, burning pain, Hyperalgesia and allodynia.

[0004] Non-steroidal anti-inflammatory drugs and narcotic analgesics such as morphine are used for the purpose of pain relief in the medical field, and more recently, antiarrhythmic drugs and anticonvulsants that are sodium channel inhibitors Has also been used for pain relief purposes.

In the case of non-steroidal anti-inflammatory drugs, the analgesic effect is not necessarily completely satisfactory, and also has side effects such as gastrointestinal disorders and kidney disorders. Narcotic analgesics such as morphine are mainly effective against nociceptive pain, but have serious problems of side effects on the digestive system, respiratory system and central nervous system. In general, these drugs are less effective against neuropathic pain. Existing sodium channel inhibitors, such as antiarrhythmic drugs such as lidocaine and mexiletine, and anticonvulsants such as carbamazepine, have come to be used for pain relief. However, these sodium channel inhibitors have central side effects such as convulsions and drowsiness, and peripheral side effects such as bradycardia, which makes it difficult to increase the dose.As a result, sufficient analgesic effects cannot be obtained. There was a problem.

[0005] As described above, an analgesic that has a useful effect in the treatment of neuropathic pain and is excellent in safety has not yet been found. Accordingly, there is a need for a sodium channel inhibitor that has a high analgesic effect especially on neuropathic pain and has reduced side effects. Such sodium channel inhibitors include the following general formula:

(In the above formula, W represents an optionally substituted C alkylene group, etc., and Z may be substituted.

1-6

C, C aromatic hydrocarbon ring group, etc., 1 is an integer from 0 to 6, R ¹ and R ² are hydrogen atoms, etc.

6-14

Show. See Patent Document 1 for details of symbols in the above formula. ) Is disclosed in International Publication No. WO01Z53288 pamphlet (hereinafter referred to as Patent Document 1).

[0006] However, in the compound disclosed in Patent Document 1, the piperidine ring has a lower alkylene group or the like (W ) Is bonded to an aromatic hydrocarbon ring group or the like (z), and is bonded to an oxodihydropyridine ring via a lower alkylene at the 1-position of the piperidine ring. The basic structure is completely different from the active ingredient in a nele inhibitor and the piperidine derivative of the present invention or a pharmaceutically acceptable salt thereof.

3; T, self formula:

[Chemical 2]

Compound (1-1) is disclosed in International Publication No. WO03Z6 3874 (hereinafter referred to as Patent Document 2) as a synthetic intermediate of compound (A) represented by compound (A) (1-1). (See Reference Example 30 in Patent Document 2). However, although Patent Document 2 describes that compound (A) has a neuronal cell protective action as a PARP inhibitor, compound (A) and compound (1) which is a synthetic intermediate thereof (1) There is no suggestion or disclosure that -1) has sodium channel inhibitory action and exhibits analgesic action on neuropathic pain.

Furthermore, the following formula:

[Chemical 3]

Compound (1-2) is disclosed in US Pat. No. 5,668,151 (hereinafter referred to as Patent Document 3) as a synthetic intermediate of Compound (B) represented by (see Example 33 of Patent Document 3). Only However, although it is described that the compound) is used for the treatment of hypertension or obesity, the compound (B) and the compound (1-2) which is a synthetic intermediate thereof have a sodium channel inhibitory action, There is no suggestion or disclosure of an analgesic effect on neuropathic pain.

Disclosure of the invention

[0009] The present invention relates to a sodium channel inhibitor having a high analgesic effect on neuropathic pain and reduced side effects, a novel piperidine derivative useful as a sodium channel inhibitor, or a pharmaceutically acceptable salt thereof. The object is to provide an acceptable salt and a pharmaceutical composition containing it as an active ingredient.

[0010] The present inventors have conducted extensive research on piperidine derivatives, and as a result, the piperidine ring is directly connected to the benzene ring or the hetero ring (A ring), and the A ring is further directly connected to the benzene ring. A cyclic piperidine derivative or a pharmaceutically acceptable salt thereof has a strong inhibitory action (activity) on sodium channels, and also against streptozotocin-induced diabetic neuropathy mice that are pathological animal models. It has been found to have a good analgesic action, and a novel tricyclic piperidine derivative in which the benzene ring and the piperidine ring are bonded at the ortho position of the benzene ring (A ring), and the A ring is a thiophene ring. The inventors have found that a novel tricyclic piperidine derivative has a particularly strong inhibitory action (activity) on a sodium channel, thereby completing the present invention. That is, according to the present invention, the following sodium channel inhibitor, a novel piperidine derivative useful as a sodium channel inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutical containing the same as an active ingredient A composition is provided.

[0011] [1] The following general formula (I):

[Chemical 4]

(The symbols in the above formula (I) have the following meanings, respectively: Ring A: a benzene ring, or a 5- or 6-membered heterocycle having 1 to 3 heteroatoms selected from N, S, and O,

RR ⁶ : the same or different, hydrogen atom, halogen atom, lower alkyl, O lower alkyl, —o-aryl, aryl, cycloalkyl, —c (= o) lower alkyl,

COOH, — C (= 0) —O—lower alkyl, C (= 0) —NH, —C (= 0) NH—low

2

Primary alkyl, C (= 0) N— (lower alkyl), OH, —O—C (= 0) —lower alkyl

2

, NH, —NH lower alkyl, N (lower alkyl), one NH—C (= 0) —low

twenty two

Piperidine derivatives represented by secondary alkyl, CN or NO) or pharmaceutically acceptable derivatives thereof.

2

A sodium channel inhibitor containing a salt as an active ingredient (hereinafter sometimes referred to as “first aspect of the invention”).

[0012] [2] The following general formula (a) or (b):

[Chemical 5]

(The symbols in the above formula (a) or (b) have the following meanings, respectively.

RR ⁶ : the same or different, hydrogen atom, halogen atom, lower alkyl, —O lower alkyl, —o-aryl, aryl, cycloalkyl, —c (= o) lower alkyl, C

OOH, one C (= 0) —O lower alkyl, one C (= 0) —NH, one C (= 0) NH lower

2

Alkyl, one C (= 0) N (lower alkyl), OH, one O—C (= 0) —lower alkyl,

2

NH, 1 NH—lower alkyl, —N— (lower alkyl), —NH—C (= 0) —lower

twenty two

Piperidine derivatives represented by rualkyl, CN or NO) or a pharmaceutically acceptable derivative thereof.

2

Salt (hereinafter sometimes referred to as "second aspect of the invention").

[0013] In [3] [2], the piperidine derivative force is represented by the following general formula (a):

(R ^ R ⁶ in formula (a), respectively. Having the same meaning as above) Ru der those represented by the piperidine derivative or a pharmaceutically acceptable salt thereof.

[4] In [2], the piperidine derivative is represented by the following general formula (b):

[Chemical 7]

(In the above formula (b),! ^-Has the same meaning as above), or a piperidine derivative or a pharmaceutically acceptable salt thereof.

[0015] [5] A pharmaceutical composition comprising the piperidine derivative or a pharmaceutically acceptable salt thereof according to any one of [2] to [4] as an active ingredient.

[6] The pharmaceutical composition according to the above [5], which is a sodium channel inhibitor.

[0017] According to the present invention, a sodium channel inhibitor having a high analgesic effect on neuropathic pain and reduced side effects, a novel piperidine derivative useful as a sodium channel inhibitor, or a pharmaceutically acceptable salt thereof. And a pharmaceutical composition containing the same as an active ingredient. The present invention (first aspect of the invention) ) Active ingredient in a sodium channel inhibitor (piberidine derivative represented by the above general formula (I) (hereinafter sometimes referred to as “active ingredient (I)”), or a pharmaceutically acceptable salt thereof. ), And a piberidine derivative represented by the above general formula (a) or (b) of the present invention (second aspect of the present invention) (hereinafter sometimes referred to as “the present compound (I)”) or The pharmaceutically acceptable salt was confirmed to be a compound having sodium channel inhibitory activity superior to mexiletine. It was also confirmed that diabetic neuropathy mice, which are pathological animal models, show good analgesic effects by oral administration.

BEST MODE FOR CARRYING OUT THE INVENTION

[0018] Hereinafter, the active ingredient (I) in the sodium channel inhibitor of the present invention (first aspect of the invention) and the compound (I) of the present invention (second aspect of the invention) will be specifically described. explain

[0019] The term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified. Examples of “lower alkyl” include C such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl and the like. Alkyl

1-6

Preferred are methyl, ethyl, propyl, butyl, tert-butyl.

[0020] N, S, O force "5-membered or 6-membered heterocycle having 1 to 3 selected heteroatoms" includes a saturated or unsaturated 5-membered or 6-membered heterocycle, Specifically, unsaturated rings such as furan, thiophene, pyrrole, pyridine, oxazole, isoxazole, thiazole, isothiazole, furazane, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine; pyrrolidine, imidazolidine, virazolidine, piperidine And saturated rings such as piperazine, morpholine, etc., preferably furan, thiophene, pyrimidine, morpholine, and particularly preferably thiophene.

[0021] Examples of the "halogen atom" include fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

[0022] "Cycloalkyl" means a 1 to 3 ring aliphatic saturated hydrocarbon ring group having 3 to 14 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. , Cyclooctyl, bicycloheptyl, bicyclooctyl, bicyclononi Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclocyclohexyl, cyclocyclohexyl, tricyclohexyl, cyclohexane, tricyclodode, and tricyclodode. Heptyl and cyclooctyl.

[0023] "Aryl" means a 1 to 3 ring aromatic hydrocarbon ring group having 6 to 14 carbon atoms, and examples thereof include phenol, naphthyl, anthryl, phenanthryl and the like. Are fuel and naphthyl.

The active ingredient (I) and the compound (I) of the present invention exist as optical isomers (optically active forms, diastereomers, etc.) or geometric isomers depending on the type of substituent. Therefore, the active ingredient (I) and the compound (I) of the present invention include those optical isomers or mixtures of these geometric isomers and isolated ones.

[0025] The active ingredient (I) and the compound (I) of the present invention can form an acid addition salt or a salt with a base. For example, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid Acid addition salts with organic acids such as maleic acid, lactic acid, malic acid, citrate, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid; inorganic such as sodium, potassium, magnesium, calcium, aluminum Salts with bases; salts with organic bases such as methylamine, ethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine, lysine, and orthotin.

[0026] Furthermore, the active ingredient (I) and the compound of the present invention (1), or a pharmaceutically acceptable salt thereof, can form hydrates, solvates such as ethanol, and crystal polymorphs. There is a case.

[0027] Furthermore, the active ingredient (I) and the compound (I) of the present invention are metabolized in vivo into the active ingredient (I) and the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof. This includes all compounds to be converted and all V prodrugs. As a group forming a prodrug of the active ingredient (I) and the present compound _{(I), p r0 g Med} 5:.. 2157-2161 or groups described in (1985), Hirokawa Shoten 1990 annual "Pharmaceuticals Development of “7th Molecular Design 163-198”. Specifically, it is a group that can be converted into primary or secondary amine, OH, HOC (= 0)-, etc. as in the present invention by hydrolysis, solvolysis, or under physiological conditions, Examples of OH prodrugs include, for example, lower alkyls that may be substituted. Lou C (= 0) 0—, optionally substituted aryl — C (= 0) 0—, ROC (= 0) —lower alkylene optionally substituted — C (= 0) 0— (R is H Or ROC (= O) may be substituted !, lower alkylene C (= O) O—, ROC (= O) lower ananolene O lower ananolene C (= 0) 0 —, ROC (= 0) c (= o) O—, ROS (= 0) — optionally substituted lower alkellene — C (= 0) 0—, phthalidyl

2

—O—, 5-methyl-1,3 dioxolene-2 on-4-rumethyloxy and the like.

[0028] Hereinafter, representative production methods, raw material synthesis and formulation of the active ingredient (I) and the compound (I) of the present invention will be described.

[0029] [Production method]

The active ingredient (I) and the compound (I) of the present invention can be produced by applying various synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. The following describes typical manufacturing methods.

[0030] [Chemical 8]

(In the above formula,! ^ ¹ to! ^ Represent the above-mentioned groups. M represents Li, MgBr or the like. Y represents an amino group such as a tert-butoxycarbol group or a benzyloxycarboro group. The same applies hereinafter.)

[0031] The active ingredient (I) and the compound (I) of the present invention can be produced by applying various synthetic methods using the characteristics based on the basic skeleton or the type of substituents. Explain the typical manufacturing method. Conventional methods such as Aryl Lithium, Aryl Grignard reagent, etc. Reaction of aryl metal and nitrogen with an oxopiperidine derivative protected with an amino protecting group (

Bioorg. Med. Chem., 10, 371-383 (2002); Tetrahedron., 21, 3331-3349 (1965), dehydration of further alcohol derivatives 0. Org. Chem., 54, 4795-4800 ( 1989); J. Org. Chem., 66, 7804-7810 (2001); J. Org. Chem., 66, 3593-3596 (2001), reduction (Bioorg. Med. Chem., 10, 371-383). (2002) and deprotection (Protective groups in Organic Synthesis, third ed., Theodora W. Greene & Peter GM Wuts, INC.).

[0032] The active ingredient (I) and the starting compound of the compound (I) of the present invention are described in the aforementioned literature (Bioorg. Med. Chem., 10, 371-383 (2002); Tetrahedron., 21, 3331-3349 ( 1965); J. Org. Chem., 5 4, 4795-4800 (1989); J. Org. Chem., 66, 7804-7810 (2001); J. Org. Chem., 66, 3 593-3596 ( 2001); Bioorg. Med. Chem., 10, 371-383 (2002); Protective groups in Organic Synthesis, third ed., Theodora W. Greene & Peter GM Wuts, INC.) And (Synlett., 3, 207- 210 (1992) and can be easily produced according to the synthesis method described in 1992.

[0033] The active ingredient (I) and the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof thus produced remain free or are simply used as a pharmaceutically acceptable salt thereof. Be released. The salt of the active ingredient (I) and the compound (I) of the present invention can be produced by subjecting the active ingredient (I) which is a free base and the compound (I) of the present invention to a usual salt formation reaction.

[0034] Isolation and purification of the active ingredient (I) thus produced and the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof include extraction, concentration, distillation, crystallization, and filtration. It is carried out by applying ordinary chemical operations such as recrystallization, various chromatographies and the like.

[0035] Various isomers can be separated by selecting an appropriate raw material compound or by utilizing a difference in physical or chemical properties between isomers. For example, optical isomers can be obtained by selecting appropriate raw materials or by resolving a racemic compound (for example, a method of optically resolving a diastereomeric salt with a general optically active acid). Can lead to sterically pure isomers.

[0036] [Prescription]

The active ingredient (I) and the compound of the present invention (1), or pharmaceutically acceptable salts thereof are generally Various commonly used formulations can be applied. The following explains the typical prescription. The pharmaceutical composition containing active ingredient (I) and compound (1) of the present invention, or one or more of pharmaceutically acceptable salts thereof as an active ingredient includes a pharmaceutically acceptable carrier. Can be used for the formulation of carriers, excipients, and other additives that are usually used in formulation, tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments It is prepared as a patch and administered orally (including sublingual administration) or parenterally.

[0037] The dosage of the active ingredient (I) and the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof is determined in consideration of the patient's symptoms, body weight, age, sex, route of administration, etc. Force determined as appropriate according to individual case Normal adult per day, 1 mg per day: LOOOmg, preferably in the range of 10 mg to 200 mg The power to be administered orally once to several times a day, adult Per person per day, in the range of lmg to 500mg, force once a day in several divided doses, or intravenously in the range of 1 to 24 hours per day. Of course, as described above, the dose varies depending on various conditions, and therefore a dose smaller than the above dose may be sufficient.

[0038] Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such a solid composition, at least one active substance contains at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polybulurpyrrolidone, Mixed with magnesium metasilicate aluminate. The composition is prepared according to conventional methods with additives other than inert diluents, eg lubricants such as magnesium stearate; disintegrants such as starch, fibrinoglycolic acid lucum; stabilization such as ratatoses An agent; it may contain a solubilizing agent such as glutamic acid and aspartic acid. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropinolecellulose, hydroxypropinolemethinolecellulose phthalate, or a gastric or enteric film.

[0039] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and generally used inert diluents. Examples include purified water and ethanol. In addition to the inert diluent, this composition contains solubilizing or solubilizing aids, wetting agents, suspending agents, etc .; sweeteners; flavoring agents; fragrances; preservatives, etc. You may have.

[0040] Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil; alcohols such as ethanol; polysorbate 80 (trade name). Such a composition further includes additives such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, extra leuth), soluble soot or solubilizing aids. May be included. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide, or irradiation. They can also be prepared by preparing a sterile solid composition and dissolving it in sterile water or sterile injection solvent before use.

[0041] Further, the active ingredient (I) and the compound of the present invention (1), or a pharmaceutically acceptable salt thereof may be used together with other drugs effective for pain. Drugs effective for pain that can be used in combination include narcotic analgesics, antipyretic analgesics, non-steroidal anti-inflammatory drugs, and the like.

Example

Next, the power to explain the present invention in more detail by way of examples The present invention is not limited to these examples. Hereinafter, production examples of the active ingredient (I) and the compound (I) of the present invention will be specifically described. In addition, the manufacture example of the raw material compound used in an Example is demonstrated as Reference Examples 1-22.

[0043] (Reference Example 1)

1-bromo 2-iodobenzene 2. Add 30 ml of Og in 30 ml of dimethoxyethane, add 15 ml of water, 1.06 g of 2,6-dimethylphenylboranoic acid, 2.25 g of sodium carbonate, and 408 mg of tetrakis (triphenylphosphine) palladium and heat for 1 week Refluxed. The resulting reaction solution was cooled to room temperature and extracted by adding jetyl ether, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated and the concentrated residue was purified by silica gel column chromatography (hexane) to obtain 1.13 g of 2,1-bromo-2,6-dimethylbiphenyl.

[0044] (Reference Example 2)

In the same manner as in Reference Example 1, the compounds shown in Table 1 were obtained. [0045] (Reference Example 3)

To a solution of 945 mg of 2-bromo4'-methoxybiphenyl in 25 ml of tetrahydrofuran was added 2.39 ml of n-butyllithium hexane solution at 78 ° C in an argon atmosphere and stirred for 20 minutes. To this was added a solution of benzyl 4-oxopiperidine 1 carboxylate (879 mg) in tetrahydrofuran (10 ml), and the mixture was stirred for 1 hour and then at room temperature overnight. The obtained reaction solution was poured into a saturated sodium chloride aqueous solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the concentrated residue was purified by silica gel column chromatography (hexyl monoacetate) to give benzyl 4-hydroxy-4- (4,1-methoxybiphenyl-2-yl) piperidine. 941 mg of 1-1 carboxylate was obtained.

[0046] (Reference Examples 4 to 14)

In the same manner as in Reference Example 3, the compounds shown in Tables 1 and 3 were obtained.

[0047] (Reference Example 15)

Magnesium 871 mg of jetyl ether 15 ml suspension in a stream of argon under ice-cooling bromine 1.38 ml was added dropwise and stirred for 30 minutes under ice-cooling, followed by stirring for about 1 hour at room temperature (reaction solution (1 )). On the other hand, to 12.5 ml of butyllithium hexane solution in an argon stream, 40 ml of a solution of 3.28 g of 3 bromo-2-phenolthiophene in −78 ° C. was dropped, and then the reaction solution (1) was dropped. After completion of dropping, the mixture was stirred at room temperature for 1 hour. The resulting reaction suspension was concentrated under an argon atmosphere (reaction liquid (2)). Add tert-butyl 4-oxopiperidine-1-carboxylate to a solution of 5.35 g of jetyl ether in 400 ml. Add dropwise the reaction solution (2) in 78 ° C and stir at -78 ° C for 1 hour. The mixture was further stirred at room temperature for 2 hours. After completion of the reaction, a saturated sodium chloride aqueous solution was added to the resulting reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate) to give tert-butyl 4-hydroxy-4- (2-phenyl-3-phenyl) piperidine— 6.35 g of 1-carboxylate was obtained as a mixture with tert butyl 4-oxopiperidine-1-carboxylate.

[0048] (Reference Example 16)

The compounds shown in Table 2 were obtained in the same manner as in Reference Example 15. [0049] (Reference Example 17)

Benzyl 4 Hydroxy 4- (4-Monobiphenyl 1-yl) Piperidine 1 1 Carboxylate 22 mg of p-Toluenesulfonic acid monohydrate is added to a solution of 250 mg of toluene and heated for 1.5 hours. Refluxed. The obtained reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate, and the organic layer was washed successively with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 230 mg of benzyl 4- (4′-methoxybiphenyl- 2 yl) 3,6 dihydropyridine 1 (2H) -powered noroxylate.

[0050] (Reference Examples 18-22)

In the same manner as in Reference Example 17, the compounds shown in Tables 2 and 3 were obtained.

[0051] (Example 1)

Benzyl 4- (4,1-methoxybiphenyl-1-yl) 3,6 Dihydropyridine 1 1 (2 H) -carboxylate 220 mg methanol 3 ml suspension in 10% palladium-activated carbon 50 mg under argon atmosphere After that, the mixture was stirred overnight at room temperature in a hydrogen atmosphere. Further, 50 mg of palladium hydroxide was added in an argon atmosphere, and the mixture was stirred at room temperature in a hydrogen atmosphere of about 3.4 atm for 2 days. The resulting reaction solution was filtered, the filtrate was concentrated, and the concentrated residue was purified by silica gel force chromatography (black mouth form-methanol-ammonia water). The purified product was dissolved in ethanol, and 0.14 ml of 4M hydrochloric acid / ethyl acetate solution was added and concentrated to obtain crystals. The obtained crystals were recrystallized from ethanol ethyl acetate to obtain 93 mg of 4 (4′-methoxybiphenyl-2-yl) piperidine monohydrochloride.

[0052] (Examples 2 to 8)

In the same manner as in Example 1, the compounds shown in Tables 4 and 5 were obtained.

[0053] (Example 9)

tert-Butyl 4-one (4-monofluorobiphenyl 2-yl) -4-hydroxypiberidine-1 carboxylate and tert-butyl 4-oxopiperidine 1 carboxylate mixture 500 mg, triethylsilane 2 ml, trifluoroacetic acid 4 ml was added and stirred at room temperature for 1 hour. The obtained reaction solution was concentrated, a saturated aqueous sodium hydrogen carbonate solution was added to the concentrated residue, and the mixture was extracted with chloroform. Filter the organic layer after drying over anhydrous sodium sulfate And the filtrate was concentrated. The concentrated residue was purified by silica gel column chromatography (black mouth formome tan-lu ammonia water) to obtain 179 mg of 4,1- (1,4-fluorobifur-lu 2 yl) -1,2,3,6-tetrahydropyridine. . 4 1 (4,1 Fluorobiphe 2 ro 2 yl) 1, 2, 3, 6-tetrahydropyridine 179 mg of ethanol in 5 ml solution, 1M hydrochloric acid solution in 1 ml, 10% palladium on activated carbon in 20 mg The mixture was stirred at room temperature for 2 hours. After filtration of the obtained reaction solution, the filtrate was concentrated, and the resulting crystal was recrystallized from ethanoyl monoruyl acetate to give 92 mg of 4- (4, 1-fluorobiphenyl-ru-2-yl) piperidine monohydrochloride. Obtained.

[0054] (Example 10-: L 1)

In the same manner as in Example 9, the compounds shown in Table 5 were obtained.

[Example 12]

tert-Butyl 4-hydroxy-4- (2,1-methylbiphenyl-2-yl) piperidine-1-carboxylate and tert-butyl 4-oxopiperidine-1-carboxylate 640 mg in ethanol 10 ml solution To the mixture, 2 ml of tetrahydrofuran and 100 mg of palladium hydroxide were added, and the mixture was stirred at room temperature for 3 days under a hydrogen atmosphere of about 3.4 atm. The resulting reaction solution is filtered, and the filtrate is concentrated. The concentrated residue is purified by silica gel column chromatography (hexane ethyl acetate) and tert-butyl 4- (2, -methylbiphenyl-2-yl) piperidine. — 1—Carboxylate 150 mg was obtained. Subsequently, tert-butyl 4- (2'methylbiphenyl-2-yl) piperidine monocarboxylate 203 mg of ethanol 2 ml of the suspension was added 4 M hydrochloric acid / ethyl acetate solution 5 ml and stirred at room temperature for 2 hours. . The resulting reaction solution was concentrated, and the crystallized residue was recrystallized using ethanol ethyl acetate to obtain 157 mg of 4- (2, -methylbiphenyl-2-yl) piperidine monohydrochloride. .

[Example 13]

tert-Butyl 4-hydroxy 1 (5 phenol 1 2-cell) piperidine 1 1-power ruboxylate and tert-butyl 4-oxopiperidine 1-carboxylate 1. 3 g, 3 ml of triethylsilane, trifluoroacetic acid 6 ml was added and stirred in a water bath for 1 hour. Concentrate the resulting reaction solution, add saturated aqueous sodium hydrogen carbonate solution to the concentrated residue, extract with chloroform, dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate. did. The concentrated residue was purified by silica gel column chromatography (black mouth form 1 methanol 1 ammonia water). After the purified product was dissolved in ethanol, 4M hydrochloric acid / ethyl acetate solution 2. Oml was added and concentrated to obtain crystals. The obtained crystals were recrystallized from ethanol-ethyl acetate to obtain 320 mg of 4- (5-phenol 2-cell) piperidine monohydrochloride.

[0057] (Examples 14 to 17)

In the same manner as in Example 13, the compounds shown in Table 6 were obtained.

[0058] Tables 1 to 6 show the chemical structural formulas and physicochemical properties of the compounds obtained in Reference Examples and Examples. In addition, the compounds described in Tables 7 to 9 can be easily obtained by using the above-mentioned production methods, reference examples, production methods of Examples, production methods known to those skilled in the art, and variations thereof. be able to.

[0059] The symbols in the table have the following meanings.

Rf .: Reference number, Ex .: Example number, Me: Methyl group, Salt: Salt, MS: Mass spectrum (FAB or ESI unless otherwise specified) mZz, NMR: Nuclear magnetic resonance spectrum (400MHz unless otherwise specified ^^ — NMR, DMSO— d, TMS internal standard) δ (ppm)

6

[0060] [Table 1]

2]

[ε 挲] [2900]

S809T0 / S00Zdf / X3d 8! · .TSSZ0 / 900Z OAV

Five]

6]

7]

[8 挲] 900]

9T0 / S00Zdf / X3d zz .TSSZ0 / 900Z OAV [¾006

[Pharmacological test]

(Sodium channel inhibition test)

Of the active ingredient (I) and the compound (I) of the present invention, the sodium channel inhibitory action of representative compounds was confirmed by [ ¹⁴ c] guanidine uptake experiments using rat brain tissue. [ ¹⁴ c] Guazine incorporation experiments were performed by modifying the method of Bonisch et al. (British Journal of Pharmacology 108, 436-442, 1993). Sodium tracer ^[14 C] guaiacolsulfonate - with Jin, induced by some base Ratorijin sodium channel activator ^[14 c] guaiacolsulfonate - measuring the inhibitory activity against the uptake of Jin into rat cerebral cortex primary neurons did. [0070] a. Preparation of rat cerebral cortex primary neuron culture system

The pregnant rat HWistar, female, 19 days of gestation) was anesthetized with ether and bleeded by carotid artery amputation. The fetus was removed from the pregnant rat, disinfected with ethanol for disinfection, and then the cerebral cortex was extracted. The cerebral cortex is digested with papain, dispersed in the culture medium, and seeded on a 96-well white plate coated with poly-L-lysine at a density of 2.5 X 10 ⁵ cells / well, and CO

The cells were cultured for 2 days at 2 beta (37 ° C, 5% CO 2).

2

[0071] b. Evaluation of test compound

Each well is attached to Atsey Buffer (135 mM Choline CI, 5 mM KCl, ImM MgSO

Four

, 5.5 mM Glucose, Img / mL BSA, lOmM Hepes-Tris, pH 7.4), and then washed with Atsy buffer for 10 minutes at 25 ° C. Thereafter, the reaction solution (test compound, [ ^W C] guanidine and 100 M veratridine) was substituted and incubated at 25 ° C. for 15 minutes. Stop the reaction by washing 3 times with cold wash buffer (135 mM NaCI, 5 mM KCl, ImM MgSO, lOmM Hepes-Tris, pH 7.4).

Four

And went by. After stirring and stirring 17 L of 0. IN NaOH to each well, a 100 / zL scintillator was added and further stirred, and the radioactivity was measured with a liquid scintillation counter. The amount of sodium channel-specific uptake in each experiment was the portion of total uptake that was inhibited by ImM mexiletine. The effect of the test compound on the sodium channel is expressed as a 50% inhibition rate (IC value) for specific uptake.

50

[0072] As shown in Table 10, the active ingredient (I) and the compound (I) of the present invention have an IC value of about 3 to 30 μΜ.

50 were more potent than mexiletine (about 70 M).

[0073] [Table 10]

(Analgesic action in streptozotocin-induced diabetic neuropathy model)

The inhibitory effect of the active ingredient (I) and the representative compound (I) of the present invention on neuropathic pain is the analgesic action in streptozotocin (STZ) -induced diabetic neuropathy mice. Confirmed by evaluation. Evaluation was carried out by partially modifying the method of Kamei et al. (Pharmacology Biochemistry & Behavior 39, 541-544, 1991).

[0075] 200 mg Zkg body weight of STZ was intraperitoneally administered to male 4-week-old ICR mice to create a diabetic neuropathy model. The tail pinch test was adopted as the method for evaluating analgesic action. That is, the analgesic action was detected as the extension time (seconds) of the latency until the force animal turned and responded with the tail pinched between cramps. On the 14th day after STZ administration, the test compound pre-administration test was conducted, and the response latency before test compound administration was measured. Only animals with a response latency of 3 seconds or less before test compound administration were subjected to the test compound evaluation test on the next day (15 days after STZ administration). Test Compound Evaluation In the test, the response latency after administration of the test compound was measured. The test compound was orally administered at 30 mgZkg 45 minutes before measuring the response latency. The analgesic action of the test compound is expressed as the latency extension (seconds) according to the formula of (response latency after test compound administration) (response latency before test compound administration).

[0076] As shown in Table 11, the active ingredient (I) and the compound (I) of the present invention exhibited a prolonged latency (seconds) of about 2 to 6 seconds and had a good analgesic action.

[0077] [Table 11]

[0078] As described above, the active ingredient (I) and the compound (I) of the present invention have a strong sodium channel inhibitory action, and are strongly analgesic in a streptozotocin-induced diabetic neuropathy model. The effect was shown.

[0079] (Evaluation of deviation from side effects)

Drugs currently used in the treatment of neuropathic pain have the problem that the frequency of side effects is high and it is difficult to increase the dose because the difference between the analgesic action dose and the side effect expression dose is small. Among the compounds of the present invention, a typical compound for detecting a side effect is that a representative compound has a property that it is difficult to cause a side effect even when administered at a high dose compared with the dose required to develop an analgesic effect. It was confirmed by the rotarod test frequently used as a law. Evaluation by Christensen et al. (Pain 93, 1 47-153, 2001). Male SD rats were used for the experiments. In each trial, the animal was placed on a rotarod device that accelerated at a constant rate of 4 rpm to 40 rpm in 5 minutes, and the time until it dropped (retention time: seconds) was measured. On the test day, each animal was first weighed and three pre-drug trials were performed. During the three trials, animals that showed a retention time of 90 seconds or longer were selected for evaluation of drug action. The selected animals were divided into groups so that the difference in the average retention time before drug administration was as small as possible between the groups. The drug was administered orally with 5 ml / kg of solvent. After the drug administration, two trials were carried out simultaneously with the anti-alodia effect measurement test in L5 / L6 spinal nerve ligated rats. For example, if the anti-allody effect was measured at 30 minutes after drug administration, trials after drug administration were conducted at 30 minutes after drug administration in the rotarod test. The average of two trials was used as the retention time after drug administration for each animal. The retention time for each group was expressed as a mean value standard error. A significant difference test between the solvent-administered group and the drug-administered group was performed using the Dmmett's test method, and a value of 0.05 was determined to be significant.

Some of the compounds of the present invention are unlikely to cause side effects even when administered at a high dose compared to the effective dose in the anti-alodynic effect measurement test in L5 / L6 spinal nerve ligated rats. There was a compound having.

(Anti-arodinian effect in L5ZL6 spinal nerve ligation rats)

One of the major symptoms in neuropathic pain is a marked decrease in the response threshold (alodinia) to tactile stimuli. The anti-oral dinergic effect of neuropathic pain of representative compounds among the compounds of the present invention was confirmed by evaluation of analgesic action in L5ZL6 spinal nerve ligated rats. The evaluation was performed by partially modifying the method of Kim and Chung (Pain 50, 355-363, 1992). Under pentobarbital anesthesia, surgery was performed to ligate the left L5 and L6 lumbar nerves of male 5 or 6 week old SD rats with silk thread. Von Freyhair test was adopted as the method for evaluating analgesic action. That is, the back of the animal's hind paw was poke with hair, and the minimum hair strength that caused a foot-lifting reaction was defined as the response threshold (log gmm) for mechanical stimulation. It was confirmed by preliminary studies that the reaction threshold of the animal's ligation foot was markedly reduced between the 7th day and the 14th day after surgery (in the state of alodya). The anti-allody effect was evaluated on any day between 7 and 14 days after surgery. Test compound On the day before product evaluation, the reaction threshold before administration of the test compound was measured. The animals were divided into 45 and 5 groups so as to reduce the difference in the mean value of the threshold values before the test compound administration and the variation within the groups. In the test compound evaluation test, the reaction threshold was measured after test compound administration. Test compounds were administered orally 30 minutes prior to reaction threshold measurements. The efficacy of the anti-alodynic action of the test compound is expressed as an ED value calculated by defining the threshold values for the surgical and non-operative foot in the solvent administration group as 0% and 100%, respectively.

50

Among the compounds of the present invention, there was a compound showing an excellent ED value. Meanwhile, mexiletine

50

The ED value was about 70mgZkg.

Claims

Claims [1] The following general formula (I)

[Chemical 1]

(The symbols in the above formula (I) have the following meanings, respectively:

Ring A: a benzene ring, or a 5- or 6-membered heterocycle having 1 to 3 heteroatoms selected from N, S, and O,

COOH, — C (= 0) —O—lower alkyl, C (= 0) —NH, —C (= 0) NH—low

2

Primary alkyl, C (= 0) N— (lower alkyl), OH, —O—C (= 0) —lower alkyl

2

, NH, —NH lower alkyl, N (lower alkyl), one NH—C (= 0) —low

twenty two

2

A sodium channel inhibitor containing a salt as an active ingredient.

[2] The following general formula (a) or (b):

[Chemical 2]

(! In the above formula (a) or (b) is the same or different and is a hydrogen atom, halogen atom, lower alkyl, —O lower alkyl, O aryl, aryl, cycloalkyl, C (= 0) — Lower alkyl, COOH, c (= o) —O—lower alkyl, c (= o) —NH, one C (= 0) NH lower alkyl, C (= 0) N (lower alkyl), OH, one O

twenty two

— C (= 0) —lower alkyl, NH, —NH lower alkyl, N (lower alkyl)

twenty two

, —NH—C (= 0) —lower alkyl, CN or NO. ) Piperidine invitation

2

A conductor or a pharmaceutically acceptable salt thereof.

In claim 2, the piperidine derivative is represented by the following general formula (a):

[Chemical 3]

(In the formula (a),! ^-Has the same meaning as described above.) A piperidine derivative or a pharmaceutically acceptable salt thereof.

In claim 2, the piperidine derivative is represented by the following general formula (b):

[Chemical 4]

(! ^ ~ In the above formula (b) has the same meaning as above) A piperidine derivative or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising the piperidine derivative according to any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.

6. The pharmaceutical composition according to claim 5, which is a sodium channel inhibitor.